Blood normally circulates through the lungs at a relatively low pressure. In pulmonary arterial hypertension (PAH) this pressure is increased, often for unknown reasons. Recent results suggest that the underlying problem in PAH may be the thickening of the muscular layer in the walls of lung arteries. At the same time, the cells that form the inner lining of blood vessels, endothelial cells, change by acquiring cell surface proteins that are not present on endothelial cells of normal vessels. We recently made the discovery that an intracellular protein known as R-Ras can counteract the types of blood vessel changes that occur in PAH. We propose to develop R-Ras into a new treatment for PAH. To enhance the delivery of the R-Ras protein to the diseased lung vasculature, we will attach a peptide signal to the R-Ras protein that will selectively deliver it to lung vessels. Once R-Ras has reached the diseased vessels, another peptide signal transports it inside the cells in the vessel wall, where it will act to prevent the changes that are believed to be the root cause of PAH. We will first test several candidate peptides for their ability to target PAH in a rat model. The selected peptides will be conjugated to R-Ras to produce PAH-targeted functional proteins. We will then test them for their effects in cell culture and select the most promising compounds. We hope to show during Phase I of the grant that we can target R-Ras to the diseased vessels and that it is active. This demonstration of feasibility would form the basis of further development of R-Ras into a novel therapy for PAH. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a disease that in its primary and secondary forms affects hundreds of thousands of Americans. The disease is progressive and serious: it can lead to the failure of the right side of the heart, the side that handles blood circulation through the lungs. The current treatments can only relieve the symptoms; 50 % of PAH patients succumb to the disease within 5 years. The new therapy we propose to develop will attack an underlying cause of PAH and may also address other vascular diseases with similar features. [unreadable] [unreadable] [unreadable]